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Review Article
DanL.Longo,M.D.,Editor

Fibrosis A Common Pathway to Organ

Injury and Failure
DonC.Rockey,M.D., P.DarwinBell,Ph.D., and JosephA.Hill,M.D., Ph.D.
From the Department of Internal Medicine, Medical University of South Carolina
(D.C.R., P.D.B.), and the Ralph H. Johnson Veterans Affairs Medical Center
(P.D.B.) both in Charleston; and the
Departments of Internal Medicine and
Molecular Biology, University of Texas
Southwestern Medical Center, Dallas
(J.A.H.). Address reprint requests to Dr.
Rockey at the Department of Internal
Medicine, Medical University of South
Carolina, 96 Jonathan Lucas St., Suite
803, MSC 623, Charleston, SC 29425, or
at rockey@musc.edu.
N Engl J Med 2015;372:1138-49.
DOI: 10.1056/NEJMra1300575
Copyright 2015 Massachusetts Medical Society.

isease-related injury in any organ triggers a complex cascade

of cellular and molecular responses that culminates in tissue fibrosis. Although this fibrogenic response may have adaptive features in the short
term, when it progresses over a prolonged period of time, parenchymal scarring
and ultimately cellular dysfunction and organ failure ensue (Fig.1).
We and others have proposed four major phases of the fibrogenic response
(Fig.2). First is initiation of the response, driven by primary injury to the organ.
The second phase is the activation of effector cells, and the third phase is the
elaboration of extracellular matrix, both of which overlap with the fourth phase,
during which the dynamic deposition (and insufficient resorption) of extracellular
matrix promotes progression to fibrosis and ultimately to end-organ failure.
The fact that diverse diseases in different organ systems are associated with
fibrotic changes suggests common pathogenic pathways (Fig.2). This wounding
response is orchestrated by complex activities within different cells in which specific molecular pathways have emerged. Cellular constituents include inflammatory cells (e.g., macrophages and T cells), epithelial cells, fibrogenic effector cells,
endothelial cells, and others. Many different effector cells, including fibroblasts,
myofibroblasts, cells derived from bone marrow, fibrocytes, and possibly cells
derived from epithelial tissues (epithelial-to-mesenchymal transition) have been
identified; there is some controversy regarding the identity of specific effectors in
different organs. Beyond the multiple cells essential in the wounding response,
core molecular pathways are critical; for example, the transforming growth factor
beta (TGF-) pathway is important in virtually all types of fibrosis.
As fibrosis progresses, myofibroblasts proliferate and sense physical and biochemical stimuli in the local environment by means of integrins and cell-surface
molecules; contractile mediators trigger pathological tissue contraction. This chain
of events, in turn, causes physical organ deformation, which impairs organ function.
Thus, the biology of fibrogenesis is dynamic, although the degree of plasticity appears to vary from organ to organ.
Although we understand many of the cellular and molecular processes underlying fibrosis, there are few effective therapies and fewer that target fibrogenesis
specifically. These facts highlight the need for a deeper comprehension of the pathogenesis of fibrogenesis and the translation of this knowledge to novel treatments.

Cel lul a r a nd Mol ecul a r Theme s in Patho gene sis

Acute and chronic inflammation often trigger fibrosis (Fig.2). Inflammation leads
to injury of resident epithelial cells and often endothelial cells, resulting in enhanced
release of inflammatory mediators, including cytokines, chemokines, and others.
This process leads to the recruitment of a wide range of inflammatory cells, in1138

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Fibrosis

Eye
Strabmisus

Pulmonary fibrosis
Restrictive lung disease
Pulmonary hypertension
Right-sided heart failure

Skin
Scleroderma
Keloid
Nephrogenic systemic fibrosis

Cardiac fibrosis
Diastolic dysfunction
Heart failure, with reduced
or preserved ejection fraction
Arrhythmia

Pancreatic fibrosis
Chronic pain
Diabetes mellitus
Malabsorption
Cancer

Cirrhosis
Portal hypertension
Ascites
Gastroesophageal varices
Hepatorenal syndrome
Hepatopulmonary syndrome
Portopulmonary syndrome

Chronic kidney disease

Hepatic encephalopathy
Hepatocellular cancer

Hypertension
Anemia
Electrolyte disturbances

Renal fibrosis

Figure 1. Fibrogenesis and Major Organ Systems.

Fibrosis is a pathologic feature of disease in virtually all organs. It has protean and often lethal consequences and
accounts for substantial morbidity and mortality. Selected organs and associated diseases are highlighted.

cluding lymphocytes, polymorphonuclear leukocytes, eosinophils, basophils, mast cells, and macrophages. These inflammatory cells elicit the
activation of effector cells,1 which drive the fibrogenic process. One example in which an inflammatory lesion drives this cycle is the interstitial
nephritis induced by nonsteroidal antiinflammatory drugs (NSAIDs), which culminates in chronic
inflammation and the activation of a fibrogenic
cascade. In addition, macrophages can play a
prominent role in interstitial fibrosis, often driven
by the TGF- pathway.2 However, some inflammatory cells may be protective. For example,
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certain populations of macrophages phagocytose

apoptotic cells that promote the fibrogenic process
and activate matrix-degrading metalloproteases.3
Fibroblasts and myofibroblasts have been identified as key fibrosis effectors in many organs,
and as such are responsible for the synthesis of
extracellular matrix proteins4 (Fig. 2). Controversy exists regarding the origin of these cells;
for example, myofibroblasts may be derived from
fibroblasts or from other mesenchymal cells,
such as pericytes.5 Epithelial-to-mesenchymal transition, in which epithelial cells give rise to mesenchymal fibrogenic cells, may play a role. However,

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Inciting injury
Epithelial
cell
Injured
epithelial cell

Basement
membrane

Recruitment of
inflammatory cells
T cells
Cellcell
interaction
Macrophage

Effector cell
Effector-cell
proliferation
NK cells

Injured
endothelial cell

Cytokines

Effector-cell
activation

Figure 2. Cellular Injury and Fibrogenesis.

In parenchymal organs, many different types of stimuli lead to epithelial-cell injury (top), which is typically followed by an inflammatory
response (shown at left). This process stimulates a fibrogenic wound-healing response that involves multiple cellular and molecular systems. At the cellular level, the recruitment of inflammatory cells is central. Inflammatory cells produce a variety of mediators, cytokines,
and other factors that are responsible for the stimulation and recruitment of other cells. Key among these cells are fibrogenic effector
cells; these cells are of mesenchymal origin and include fibroblasts, fibrocytes, tissue-specific pericytes and myofibroblasts, and fibroblasts derived through epithelial-to-mesenchymal transition. These effectors produce a variety of extracellular matrix proteins, which
themselves may modify the wound milieu, often stimulating fibrogenic effector cells in an autocrine fashion. Indeed, in most organ systems, autocrine loops in fibrogenic effector cells are prominent. Cellcell interactions lead to further activation of effector cells. Effector
cells produce a variety of extracellular matrix proteins, peptides, cytokines, and growth factors, all of which may lead to autocrine stimulation (see the right side of the figure), typical of most organ systems. Many forms of injury also lead to the activation and transformation of other cells, such as specialized endothelial or tissue-specific cells. Injury to these cells in turn leads to a variety of downstream
effects, including activation of fibrogenic effector cells. NK denotes natural killer.

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Fibrosis

Cytokines

Growth
factors

Integrins
TGF-
receptor

Vasoactive
peptides
Extracellular matrix
biosynthesis

Fibrogenic
effector cell
MAPKs
Rho/ROCK
SMADs
Integrin-linked
kinase

Nucleus
Figure 3. Molecular Pathways in Fibrosis.
Fibrogenesis in multiple tissues is effected by a number of signaling cascades. These cascades (not shown) are often triggered by the exposure of effector cells to circulating or locally produced molecules that stimulate the biosynthesis and secretion of extracellular matrix proteins. The extracellular matrix itself may also stimulate fibrogenesis
through activation of integrin signaling. Examples of major pathways are shown. MAPK denotes mitogen-activated
protein kinase, ROCK Rho-associated protein kinase, and TGF- transforming growth factor .

the importance of epithelial-to-mesenchymal transition has been actively debated.6-9

The matrix proteins that compose the fibrotic
scar, which are highly conserved across tissues,
consist predominantly of interstitial collagens
(types I and III), cellular fibronectin, basementmembrane proteins such as laminin, and other,
less abundant elements. In addition, myofibroblasts, which by definition are cells that express
smooth-muscle proteins, including actin (ACTA2),
are contractile.10 The contraction of these cells
contributes to the distortion of parenchymal architecture, which promotes disease pathogenesis
and tissue failure.
The molecular processes driving fibrosis are
wide-ranging and complex (Fig. 3). The TGF-
cascade, which plays a major role in fibrosis, involves the binding of a ligand to a serinethreonine kinase type II receptor that recruits and
phosphorylates a type I receptor. This type I receptor subsequently phosphorylates SMADs, which
function as downstream effectors, typically by
modulating target gene expression. Although the
TGF- superfamily, which involves multiple signaling cascades, is too complex to review in detail
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here (see Massagu11), its diversity highlights the

complexity of the regulation of fibrosis.
TGF- is a potent stimulator of the synthesis
of extracellular matrix proteins in most fibrogenic cells. TGF- is synthesized and secreted by
inflammatory cells and by effector cells, thereby
functioning in both an autocrine and paracrine
fashion. The complexity of the TGF- system is
illustrated by its interactions with other cell-signaling pathways.12 For example, TGF- stimulates
sonic hedgehog signaling in lung fibroblasts, and
sonic hedgehog signaling, in turn, regulates fibroblast function.13 Another example of the complexity of the TGF- system emerges from study of
the extracellular activation of TGF- in an inactive complex with a latency-associated peptide,
which is subsequently activated by the v6 integrin.14
The molecular systems involved in fibrosis are
so expansive as to preclude a detailed discussion
(see Fig. 3 for an overview of several important
molecular pathways). Platelet-derived growth
factor (PDGF), connective-tissue growth factor
(CTGF), and vasoactive peptide systems (especially
angiotensin II and endothelin-1)15 play important

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roles. Among vasoactive systems, endothelin plays

a role in fibrosis in virtually all organ systems,
acting through G-proteincoupled endothelin-A
or endothelin-B cell-surface receptors or both.16
Furthermore, angiogenic pathways may be important in fibrosis.17 Finally, it is clear that integrins, which link extracellular matrix to cells,
are critical in the pathogenesis of fibrosis.18,19
When injury and inflammatory responses are
abrogated, resorption of extracellular matrix proteins occurs, promoting organ repair. When
chronic injury persists, the unremitting activation of effector cells results in the continuous
deposition of extracellular matrix, progressive
scarring, and organ damage. Thus, fibrogenesis
involves the interplay between factors that promote the biosynthesis, deposition, and degradation
of extracellular matrix proteins. Typically, matrix
synthesis is counterbalanced by matrix-degrading
metalloproteases.3,20,21 In addition, fibrogenesis is
governed by pathways that eliminate effectors
(e.g., by means of senescence, apoptosis, or autophagy). For example, the apoptosis of hepatic
stellate cells is associated with the reversal of
fibrosis.22
An understanding of the role of genetics in
the pathogenesis of fibrosis is emerging. For instance, in the kidney, fibrosis is a prominent feature of karyomegalic interstitial nephritis, which is
caused by mutations in the gene encoding Fanconi
anemia-associated nuclease 1 (FAN1).23 In the liver,
PNLAP3 is important in fibrosis that is mediated
by ethanol and associated with fatty liver disease.24,25 A number of candidate genes may be important in cases of fibrosis that are mediated by
infection with hepatitis C virus (HCV).26 Mutations
in TERT (c:2768CT), the gene encoding telomerase reverse transcriptase, and MUC5B, which encodes mucin, are associated with pulmonary fibrosis.27-29
The epigenetic regulation of gene expression,
which includes but is not limited to DNA methylation, post-translational modifications of the histone protein constituents of chromatin, and regulatory noncoding RNAs (e.g., microRNAs [miRs]),
is important in fibrosis. For example, fibroblasts
from patients with idiopathic pulmonary fibrosis have been found to have global changes in
DNA methylation, changes that are not seen in
fibroblasts from normal lungs.30 The miRs, which
play an ever-expanding role in gene regulation,
are also involved in the pathogenesis of fibrosis.
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In diabetic nephropathy, TGF- promotes the expression of miR-192, which results in collagen deposition,31 and miR-19b regulates TGF- signaling
in hepatic stellate cells.32 In the heart, miR-21,
miR-29, miR-30, and miR-133 participate in the
remodeling of the myocardial matrix.33

Mech a nisms a nd A dv er se
Cl inic a l Effec t s
Cardiac Fibrosis

The heart undergoes extensive structural and functional remodeling in response to injury, central to
which is the hypertrophy of cardiac myocytes,
with excessive deposition of extracellular matrix.34
Myocardial fibrosis is commonly categorized as
one of two types: reactive fibrosis or replacement
fibrosis. Reactive fibrosis occurs in perivascular
spaces and corresponds to similar fibrogenic responses in other tissues; replacement fibrosis occurs at the site of myocyte loss.
In the heart, fibrosis is attributed to cardiac
fibroblasts, the most abundant cell type in the
myocardium. These cells are derived from fibroblasts that are native to the myocardium, from
circulating fibroblasts, and from fibroblasts that
emerge from epithelial-to-mesenchymal transition.35,36 All these cell types proliferate and differentiate into myofibroblasts in response to
injury (Fig.2), a process that is driven by classic
factors such as TGF-1, endothelin-1, and angiotensin II.37 Cross-talk and feedback also occur
between cells in this case, between activated
fibroblasts and cardiomyocytes which further
fuel fibrogenesis.38
Cardiac fibrosis contributes to both systolic and
diastolic dysfunction and to perturbations of electrical excitation; it also disrupts repolarization
(Fig.1).39 Proarrhythmic effects are the most
prominent. Collagenous septa in the failing heart
contribute to arrhythmogenesis by inducing a
discontinuous slowing of conduction.40 Areas of
arrhythmogenic fibrosis slow conduction through
junctions in the heterocellular gap that couple
fibroblasts and cardiomyocytes.41 Endocardial
breakthrough of microreentrant circuits occurs as
a result of the heterogeneous spatial distribution
of fibrosis42 and the triggering of activity caused
by the depolarization of myocytes by electrically
coupled myofibroblasts.43
Fibrotic scarring in the heart correlates strongly with an increased incidence of arrhythmias

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Fibrosis

and sudden cardiac death.44 For example, a 3%

increase in the extracellular volume fraction of
fibrous tissue (measured by means of magnetic
resonance imaging after the administration of
gadolinium) is associated with a 50% increase in
the risk of adverse cardiac events.45
Hepatic Fibrosis

Hepatic fibrosis typically results from an inflammatory process that affects hepatocytes or biliary
cells. Inflammation leads to the activation of effector cells, which results in the deposition of
extracellular matrix. Although a variety of effectors synthesize extracellular matrix in the liver,
hepatic stellate cells appear to be the primary
source of extracellular matrix. Abundant evidence
suggests that the stellate cell is pericyte-like, undergoing a transformation into a myofibroblast in
response to injury.10
In the liver, multiple cell types, including stellate cells, endothelial cells, Kupffer cells, bile-duct
cells, and immune cells, orchestrate the cellular
and molecular response to injury.46 Numerous molecular pathways, similar to those found in other
organs, are involved. A pathway that appears to
be unique to the liver involves toll-like receptor 4
(TLR4)47; TLR4 is activated on the surface of stellate cells by intestinal bacterial lipopolysaccharides derived from the gut (i.e., translocated bacteria), triggering cell activation and fibrogenesis
and thereby linking fibrosis to the microbiome.48
TLR4 expression is associated with portal inflammation and fibrosis in patients with fatty liver
disease.49
The end result of hepatic fibrogenesis is cirrhosis, an ominous parenchymal lesion that underlies
a wide range of devastating complications that
have adverse effects on survival (Fig.1). Portal
hypertension, a devastating result of injury, develops during the fibrogenic response after disruption of the normal interaction between sinusoidal endothelial cells and hepatic stellate cells;
the resulting activation and contraction of pericyte-like stellate cells leads to sinusoidal constriction and increased intrahepatic resistance. This
increase in resistance in turn activates abnormal
signaling by smooth-muscle cells in mesenteric
vessels. An increase in angiogenesis and collateral
blood flow follows, resulting in an increase in
mesenteric blood flow and a worsening of portal
hypertension.50 The major clinical sequelae of portal hypertension, variceal hemorrhage and ascites,

emerge relatively late, after the portal pressure

rises to a hepatic venous pressure gradient of more
than 12 mm Hg.50
Renal Fibrosis

Events that initiate renal fibrosis are diverse, ranging from primary renal injury to systemic diseases.51,52 The kidneys are susceptible to hypertension and diabetes, the two leading causes of
renal fibrosis. As is true in other organs, fibrosis
of the kidney is mediated by cellular elements
(e.g., inflammatory cells) and molecular elements
(e.g., cytokines, TGF-1, CTGF, PDGF, and endothelin-1) (Fig.2 and 3).51-54 The intrarenal renin
angiotensinaldosterone axis is particularly important in hypertension-induced fibrosis.54
The kidney has a unique cellular architecture
that consists of the glomeruli, tubules, interstitium, and capillaries. Injury at any of these sites
triggers the deposition of extracellular matrix.37
The location of the initial injury is an important
determinant of the clinical consequences. Injuries that initially target glomeruli elicit patterns
of disease that are different from those that are
elicited by injuries to the tubularinterstitial environment. For example, NSAIDs, urinary obstruction, polycystic kidney disease, and infections
can provoke tubulointerstitial fibrosis,43 whereas
glomerular immune deposition (e.g., the deposition of IgA) leads to glomerulonephritis.44 Glomeruli and podocytes are sensitive to systemic and
local immunologic insults45; high glomerular capillary pressure, exacerbated by systemic hypertension and diabetes, leads to proteinuria, the
activation of cytokines and complement, and the
infiltration of immune cells, resulting in epithelial cell and interstitial fibrosis.46
Glomerular fibrosis, regardless of the cause,
diminishes renal blood flow, which leads to
hypoxia and the activation of hypoxia-inducible
factor 1, which in turn triggers nephron collapse
and fibrotic replacement by means of rarefaction.47
The renal interstitium and capillaries contribute
substantially to tubulointerstitial disease, as peritubular pericytes migrate into the interstitium,
where they are transformed into myofibroblasts.48
Regardless of the initiating insult, renal fibrosis leads to loss of function and organ failure
(Fig.1). Homeostasis can be maintained with a
glomerular filtration rate as low as approximately
10% of the normal rate. As the mechanisms maintaining homeostasis are progressively disrupted,

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anemia develops and the regulation of electrolyte blasts and myofibroblasts are activated through
balance and pH is disrupted.
the TGF-SMAD signaling pathway.60 Nephrogenic systemic fibrosis, a debilitating condition
Pulmonary Fibrosis
that is marked by widespread organ fibrosis, ocPulmonary fibrosis occurs in association with a curs in patients with renal insufficiency who have
wide range of diseases, including scleroderma (sys- been exposed to gadolinium-based contrast matemic sclerosis), sarcoidosis, and infection, and terial. Initial systemic inflammatory-response
as a result of environmental exposures (e.g., silica reactions and the reaction of gadolinium (Gd3+)
dust or asbestos), but in most patients it is idio- ions with circulating proteins and heavy metals
pathic and progressive. Idiopathic pulmonary lead to the deposition of insoluble elements in
fibrosis is characterized by progressive fibrosis tissue.61 Since no effective therapies have been
without substantial inflammation.55 Its patho- identified, prevention is key.61 A recently recoggenesis appears to be unlike that of other fibros- nized IgG4-related disease appears to involve
ing diseases and is poorly understood. Injury to autoimmune-driven inflammation that provokes
alveolar epithelial cells activates pulmonary fibro- fibrosis in multiple organs, including the pancreas,
blasts, provoking their transformation to matrix- retroperitoneum, lung, kidney, liver, and aorta.62
producing myofibroblasts.56 Activated lung fibroblasts may cause apoptosis of alveolar cells, which
Ther a py
leads to further fibroblast activation and a vicious
cycle of injury and effector-cell activation (Fig.2). Fibrosis and resultant organ failure account for
Research has focused on TGF- signaling (Fig.3)57 at least one third of deaths worldwide.63 Since
and the interstitial pericytes present in lung fi- fibrosis is common and has adverse effects in all
brosis.58
organs, it is an attractive therapeutic target. ConPulmonary fibrosis is characterized by paren- trary to the widely held perception that scar tissue
chymal honeycombing, reduced lung compliance, is permanent, the available evidence points to the
and restrictive lung function (Fig.1). Fibrosis of highly plastic nature of organ fibrosis; it is not
the interstitial spaces hinders gas exchange, cul- irreversible scar but an actively remodeled tisminating in abnormal oxygenation and clinical sue component that can, under certain circumdyspnea. Progressive pulmonary fibrosis also leads stances, regress. Fibrosis occurs by means of a
to pulmonary hypertension, right-sided heart fail- dynamic process that involves the synthesis and
ure, and ultimately respiratory failure.
deposition of extracellular matrix, and its reversion occurs by means of the elimination of efOther Forms of Fibrosis
fector cells and shifts in the balance of matrix
Fibrosis also occurs in the joints, bone marrow, synthesis and degradation (Fig.4). Although it is
brain, eyes, intestines, peritoneum and retroperi- not clear what pathogenic or clinical factors protoneum, pancreas, and skin, and in these cases mote reversibility, the regression of fibrosis has
is driven by typical cellular and molecular pro- been shown to lead to improved clinical outcomes.
cesses (Fig.2 and 3). Retroperitoneal fibrosis is Elimination of the inciting stimulus is the first
a rare condition characterized by inflammation and most efficacious approach.
and fibrosis in the retroperitoneal space; most
Fibrosis of parenchymal tissue usually procases are idiopathic, but secondary causes include gresses slowly, which suggests that therapy may
drugs, infections, autoimmune and inflammatory be required for extended periods; slowing the prostimuli, and radiation. Patients may present with gression of fibrosis may be a more realistic therapain, and the major clinical sequelae of this con- peutic goal than eliminating it. One of the chaldition are related to its involvement with struc- lenges in assessing the therapeutic response is that
tures in the retroperitoneum, including arteries there are few noninvasive means of measuring fi(leading to acute and chronic renal failure) and brosis (e.g., blood or imaging tests; biopsy is typiureters (leading to hydronephrosis). Currently, cally the most reliable approach) or monitoring the
treatment of this primary fibrosing disorder is effects of therapeutic intervention.
not available. In certain cancers, fibrosis is linked
The best indication that fibrosis is reversible
to TGF--integrin signaling.59 In scleroderma, the and that this reversibility has positive effects on
prototypical fibrosing skin disease, skin fibro- clinical outcomes is based on the treatment of
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Fibrosis

Injury and inflammation

Cytokines
Growth factors
Vasoactive peptides

Removal of profibrotic stimulus

Antifibrotic therapy
MMP activation

Figure 4. Reversibility of Fibrosis.

Fibrosis is a remarkably plastic process in which there is dynamic interplay between extracellular matrix protein deposition and degradation. For instances in which degradation overtakes deposition, tissue fibrosis can be reversed.
Often, the removal of the inciting stimulus is sufficient, and in some instances therapeutic interventions targeting
the underlying disease process may help to reverse the fibrogenic process. MMP denotes matrix metalloproteinase.

liver disease64; in patients with cirrhosis who are

infected with hepatitis B virus (HBV), antiviral
therapy reduces fibrosis, reverses cirrhosis,65 and
reduces the incidence of clinical complications.66
Pirfenidone has been shown to slow the reduction in forced vital capacity and reduce mortality, raising the possibility of a reversal in fibrosis.
Often, promising preclinical studies are not
borne out in clinical trials in terms of both expected efficacy and unexpected side effects. Thus,
at the current time, specific antifibrotic therapies are limited (see Table 1, which summarizes
core concepts from large, completed clinical trials targeting fibrosis in humans [including both
positive and negative results], and Table S1 in the
Supplementary Appendix, which includes more
detailed information about completed clinical trials and is available with the full text of this article
at NEJM.org). Several agents targeting specific
fibrotic pathways in the liver and the lung have
been examined, placing the studies of the liver
and lung ahead of studies of other organ systems
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in terms of the goal to specifically confront fibrosis. Novel approaches to the treatment of fibrosis
that are based on an extensive body of preclinical data are anticipated in the coming years (see
Table S2, which highlights early phase trials that
target less well established, although potentially
important, pathways in fibrosis).
Heart

Pharmacologic therapies in clinical use for heart

failure that target the primary underlying disease
appear to have a secondary effect on fibrosis.
Examples include angiotensin-convertingenzyme
(ACE) inhibitors, statins, aldosterone antagonists,
and emerging therapies, such as histone deacetylase inhibitors. Such therapies, which are known
to promote beneficial reverse remodeling, ameliorate fibrosis, reduce the burden of ventricular
arrhythmia, slow the rate of ventricular tachycardias,93,94 and reduce the incidence of sudden
death.39
A promising idea for the treatment of cardiac

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Table 1. Pathways and Processes in Fibrogenesis and Current Treatments.*

Organ

Pathways and Processes

Diseases

Drugs

Summary of Effectiveness

Source of Data

Heart

Aldosterone antagonism, TGF- antagonism, RAS inhibition,

cGMP inhibition, inhibition of cholesterol synthesis, inhibition of
Na-K-Cl cotransporter

Heart failure, cardiomyopathy, hypertrophic cardiomyopathy, cardiomyopathy induced by type 2 diabetes, heart failure or cardiomyopathy induced by
hypertension

Spironolactone, epler
enone, canrenone, pirfenidone, sildenafil,
statins, ACE inhibitors,
ARBs, torsemide, MRAs

ACE inhibitors, ARBs, and

MRAs are associated with
decreased fibrosis on MRI
and decreased arrhythmogenesis (the latter suggests effects of drugs on
fibrosis)

Kosmala et al.,67 Giannetta et al.,68 Antonopoulos et al.,69

Roubille et al.,70
TORAFIC Investigators Group71

Liver

RAS inhibition, inhibiMany diseases of the liver

tion of collagen synthesis, inhibition of effectorcell fibrogenesis, inhibition of oxidative stress,
signaling of PPAR
-agonists

ACE inhibitors, ARBs,

colchicine, interferon
-1b, vitamin E, pioglitazone, farglitazar

Specific antifibrotic agents

listed have generally been
ineffective in halting or
reversing fibrosis

Sanyal et al.,72 Kim et

al.,73 Kershenobich et
al.,74 Morgan et al.,75
Muir et al.,76 Pockros
et al.,77 McHutchison
et al.78

Kidney

RAS inhibition, aldoste- Primarily renal diseases

ACE inhibitors, ARBs,
rone antagonism, TGF- related to hypertension or spironolactone, pirfeniantagonism, Nrf2
diabetes
done, bardoxolone
pathway

ACE inhibitors and ARBs

are moderately effective in
slowing progression of diabetic nephropathy (indirectly suggesting effects
on fibrosis)

Lambers Heerspink
et al.,79 Ruggenenti et
al.,80 Bonventre,81
Guney et al.,82 Sharma et al.,83 de Zeeuw
et al.84

Lung

TGF- antagonism, direct inhibition of effector-cell fibrogenesis,

multikinase inhibition,
inhibition of oxidative
stress

Primarily idiopathic pulmonary fibrosis

Pirfenidone and nintedanib led to improvements in clinical outcomes

Raghu et al.,85-87 King

et al.,88 Richeldi et
al.,89 Martinez et al.90

Skin

Endothelin-receptor antagonism, multikinase

inhibition

Scleroderma, nephrogenic Bosentan, imatinib

systemic fibrosis
mesylate

Small studies show modest effects

Kuhn et al.,91 Kay and

High92

Pirfenidone, interferon
-1b, bosentan, ambrisentan, macitentan, nintedanib, acetylcysteine

* ACE denotes angiotensin-converting enzyme, ARB angiotensin-receptor blocker, cGMP cyclic guanosine monophosphate, MRA mineralocorticoid-receptor antagonist, MRI magnetic resonance imaging, Nrf2 nuclear factor erythroid 2related factor, PPAR peroxisome proliferatoractivated receptor, RAS reninangiotensin system, and TGF- transforming growth factor beta.
Detailed information about specific trials is provided in Table S1 in the Supplementary Appendix.

fibrosis is based on the premise that cardiac fibroblasts can be reprogrammed into cardiomyocyte-like cells95,96 (Table S2 in the Supplementary
Appendix) that would promote normal tissue regeneration; in a murine model of myocardial
infarction and fibrosis, the retroviral expression
of specific transcription factors in the myocardium reprogrammed cells that acquired spontaneous contractile and electrophysiological properties resembling those of cardiomyocytes, leading
to global improvements in contractile function.
It is not yet known whether this type of therapy
can be used in humans.

This approach involves the use of ACE inhibitors

and angiotensin-receptor blockers that ameliorate renal damage and fibrosis through multiple
pathways, including the suppression of the actions of TGF-.79 Therapies based on the antagonism of aldosterone that make use of mineralocorticoid receptor antagonists have been shown
to inhibit or slow the progression of fibrosis in
humans.97 Novel approaches to the treatment of
fibrosis of the kidneys include those that target
bone morphogenetic protein-7, NADPH oxidase
(NOX) (NOX1 and NOX4), and the SMAD3 and
SMAD4 pathways (Table S2 in the Supplementary
Appendix).98

Kidney

Like the therapies used to treat cardiac fibrosis,

those typically used to prevent renal fibrosis target the underlying disease processes and as such
involve the treatment of hypertension and diabetes. One target is the reninangiotensin system.
1146

Liver

The process of hepatic fibrosis is dynamic. Since

hepatocytes are capable of regeneration, liver
fibrosis may be especially amenable to therapeutic intervention, and even cirrhosis can be re-

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Fibrosis

versed.66,99-101 Eradication of HCV infection, antiviral therapy for HBV infection, glucocorticoid
therapy for autoimmune hepatitis, phlebotomy
for hemochromatosis, relief of biliary obstruction,
and cessation of alcohol consumption in alcoholic hepatitis each clearly reverses fibrotic change,
and many of these treatments improve clinical
outcomes.66,99,100,102
A number of potential antifibrotic therapies
targeting specific pathways have been studied in
human liver disease (Table S2 in the Supplementary Appendix). For example, colchicine suppresses
collagen secretion and theoretically prevents fibrosis.46 Interferon -1b and the peroxisome
proliferator-activated receptor ligand, farglitazar, which inhibit stellate cell-mediated fibrogenesis, were studied in patients infected with
HCV that was unresponsive to primary antiviral
therapy, but no beneficial effects on fibrosis
were noted.46 Other agents, including polyenephosphatidyl choline, silymarin, and ursodeoxycholic acid, have similarly shown no benefit.46
Vitamin E had modest effects on histologic fibrosis in patients with nonalcoholic steatohepatitis.72
Lung

The lung presents special challenges with regard

to therapy targeting fibrosis. On the one hand,
the lung has easily measured clinical features that
allow for assessment of lung function, a surrogate for fibrosis. On the other hand, pulmonary
fibrosis appears to be less dynamic than fibrosis
occurring in other organ systems. Multiple therapies have been tested for pulmonary fibrosis,
especially for idiopathic pulmonary fibrosis. Interferon -1b showed efficacy in preclinical studies but showed no benefit in human clinical trials.85 Endothelin-receptor antagonists have also
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